This multicenter/multinvestigator-initiated proposal will investigate the biology of human neural stem cells (hNSCs) following transplantation into the subhuman primate brain. Particular attention is directed at the hypothesis that these cells can fully normalize parkinsonism in monkeys resulting from MPTP lesions. Three related hypotheses will thus be investigated. The first is that hNSCs will survive in the normal monkey brain without immunological rejection or destructive overgrowth. Next, the proposal will test the hypothesis that hNSCs can reverse MPTP-associated motor deficits and that the presence of dopamine injury will influence the distribution and fates of these donor cells. The last part of the project is intended to demonstrate that genetic engineering of hNSCs can improve the functional reversal of parkinsonism by modifications that (a) increase the yield of differentiated dopaminergic cells via a pivotal transcription factor, (b) express GDNF, and (c) overexpress the adhesion molecule L1 which influences migration and distribution of cells thereby possibly permitting a more normal dopaminergic circuitry to be reconstructed. These studies will entail a wide spectrum of contemporary and multidisciplinary methods in neuroanatomy, molecular biology, and behavioral assessment coupled with advanced clinical diagnostic approaches.